ABSTRACT This is a new application for a K24 award for Carolyn S. Calfee, MD, Associate Professor of Medicine and Anesthesia at the University of California, San Francisco. Dr. Calfee is a physician specializing in pulmonary and critical care medicine who is strongly committed to a career in patient-oriented research (POR) and to mentoring the next generation of translational scientists. In the 8 years since completing her fellowship, she has developed a well-funded independent research program focused on improving our understanding of the pathogenesis of the acute respiratory distress syndrome (ARDS), a common cause of respiratory failure in critically ill patients with nearly 200,000 cases per year in the US alone and mortality rates of 30-40%. This K24 award will allow Dr. Calfee to achieve two principal goals: (1) to use the tools of molecular epidemiology to improve our understanding of the pathogenesis of human ARDS, with a focus on ARDS risk factors and subphenotypes; and (2) to further develop her skills in mentoring trainees in POR in ARDS while expanding her time devoted to mentoring. Dr. Calfee is at an ideal stage in her career for a K24 award, since providing dedicated protected time for mentoring in POR would allow her to expand her current research program, expand and protect her time dedicated to mentoring, and obtain further training in mentoring skills. Obtaining a K24 award at this critical mid-career stage is vital to supporting Dr. Calfee's career in POR and protecting her ability to continue mentoring trainees in this challenging funding climate. New research to be supported by this award will build on Dr. Calfee's extensive track record in pathogenesis-oriented studies of molecular phenotypes of ARDS, providing tangible support for a promising new direction in her research as well as a wealth of opportunities for trainees. Specifically, this award will support investigation of the novel hypothesis that ARDS contains two distinct subphenotypes (also known as ?endotypes?).42 Dr. Calfee recently identified and validated the presence of two distinct endotypes of ARDS in three large randomized controlled trials.16 These endotypes had strikingly different clinical characteristics, biomarker profiles, and clinical outcomes, and significant endotype-specific treatment responses were identified within a clinical trial previously thought to be ?negative.? However, because these endotypes were identified in the setting of randomized controlled trials, using a narrow set of clinical and biological data, it remains unknown whether an expanded set of clinical characteristics and biomarkers would contribute significantly to ARDS endotype identification. Likewise, it remains unknown whether patients can transition between ARDS endotypes over the course of their illness and how the biology of each endotype evolves over the first several days of ARDS. The research proposed for this award will directly address these gaps in knowledge about ARDS endotypes, so as to improve our ability to design personalized therapies tailored to the biology of disease for critically ill patients with ARDS.